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Epigenetic regulation of hypoxia inducible factor in diseases and therapeutics

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Abstract

Hypoxia-inducible factors (HIFs) are master regulators of angiogenesis and cellular adaptation in hypoxic microenvironments. Accumulating evidence indicates that HIFs also regulate cell survival, glucose metabolism, microenvironmental remodeling, cancer metastasis, and tumor progression, and thus, HIFs are viewed as therapeutic targets in many diseases. Epigenetic changes are involved in the switching ‘on’ and ‘off’ of many genes, and it has been suggested that the DNA hypermethylation of specific gene promoters, histone modifications (acetylation, phosphorylation, and methylation) and small interfering or micro RNAs be regarded epigenetic gene targets for the regulation of disease-associated cellular changes. Furthermore, the hypoxic microenvironment is one of the most important cellular stress stimuli in terms of the regulation of cellular epigenetic status via histone modification. Therefore, drug development and therapeutic approaches to ischemic diseases or cancer for targeting HIFs by modulation of epigenetic status become an attractive area. Here, the authors provide a review of the literature regarding the targeting of HIF, a key modulator of hypoxic-cell response under various disease conditions, by modulating histone or DNA using endogenous small RNAs or exogenous chemicals.

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Abbreviations

5-aza-dC:

5-Aza-deoxycitidine

ARD1:

Arrest-defective-1

CBP:

CREB binding protein

CpG:

Cytosine-preceding-guanosine

DNMT:

DNA methyltransferases

FIH:

Factor inhibiting HIF-1

HDAC:

Histone deacetylases

HIF:

Hypoxia-inducible factor

HRE:

Hypoxia response element

MAPK:

Mitogen-activated protein kinase

MBD:

Methyl-CpG-binding domain proteins

miRNA:

Micro-RNA

mTOR:

Mammalian target of rapamycin

mtROS:

Mitochondrial reactive oxygen species

ncRNA:

Non-coding RNA

ODDD:

Oxygen dependent degradation domain

PHD:

Prolyl hydroxylase domain protein

pVHL:

von Hippel-Lindau protein

RCC:

Renal cell carcinoma

RISC:

RNA-induced silencing complex

RNAi:

RNA interference

siRNA:

Small interfering RNA

TSA:

Trichostatin A

VEGF:

Vascular endothelial growth factor

GLUT:

Glucose transporter

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Acknowledgments

This study was supported by the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (Grant No: A112026; to SL and YML), and by a Grant from the Kyungpook National University Research Fund (2012 to YML).

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  1. School of Life Sciences and Biotechnology, College of Pharmacy, Kyungpook National University, Daegu, 702-701, Republic of Korea

    Minh Phuong Nguyen

  2. Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, 702-701, Republic of Korea

    Sangkyu Lee & You Mie Lee

  3. Vascular Network Research Lab, Vascular Homeostasis Regulation Lab (BRL), College of Pharmacy, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 702-701, Republic of Korea

    You Mie Lee

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  1. Minh Phuong Nguyen
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Nguyen, M.P., Lee, S. & Lee, Y.M. Epigenetic regulation of hypoxia inducible factor in diseases and therapeutics. Arch. Pharm. Res. 36, 252–263 (2013). https://doi.org/10.1007/s12272-013-0058-x

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